[unreadable] [unreadable] Emerging evidence suggests a relationship between obesity and asthma, although the precise nature of this relationship is not known. While obesity may increase airway inflammation or physiologic impairment, thereby elevating the risk of incident asthma or causing a more severe asthma phenotype, it is also possible that the effects of obesity on individuals with asthma are exerted not by alterations in airway inflammation per se, but rather by associated systemic inflammatory processes which attenuate the response to controller therapies such as inhaled corticosteroids. On the basis of preliminary studies demonstrating evidence of glucocorticoid (GC) insensitivity and systemic inflammation in overweight and obese asthmatics, we postulate that the systemic inflammatory state associated with obesity may have important biological effects on prognosis and response to therapy in asthma, in part by mediating the development of GC insensitivity. We propose to test the following interrelated hypotheses in a time-sensitive ancillary study complementing 2 upcoming clinical trials of the Asthma Clinical Research Network: Hypothesis 1: Overweight/obese asthmatics are more likely than asthmatics of normal weight ("lean asthmatics") to manifest GC insensitivity. Associated specific aims will determine: 1) immunologic response to GCs of peripheral blood mononuclear cells (PBMC) from overweight/obese vs. lean asthmatics, 2) expression of biomarkers of GC insensitivity in induced sputum cells from these groups and 3) if biomarkers of GC insensitivity are predictive of attenuated response to inhaled corticosteroid (ICS) therapy. Hypothesis 2: Overweight/obese asthmatics are more likely than lean asthmatics to demonstrate systemic inflammation, resulting in increased expression of interleukin (IL)-6, tumor necrosis factor-alpha (TNF-?) and other proinflammatory cytokines and leading to GC insensitivity. Associated specific aims will determine: 1) if cytokines and other biomarkers of systemic inflammation (IL-6, TNF-?, leptin, CRP) are increased in overweight/obese vs. lean asthmatics, 2) if cytokines and other biomarkers of systemic inflammation found to be elevated in overweight/obese asthmatics reduce GC sensitivity of PBMCs from GC- sensitive asthmatics and 3) determine if biomarkers of systemic inflammation are predictive of attenuated response to ICS therapy. Hypothesis 3: Differences in response to ICS therapy between overweight/obese and lean asthmatics are due to GC insensitivity and/or systemic inflammation and not to baseline differences in asthma severity (as defined by physiologic, clinical or airway inflammatory characteristics). Associated specific aims will: 1) quantify the relationship between overweight/obesity and asthma severity in subjects with persistent asthma and 2) determine if overweight/obesity, when controlled for the degree of GC insensitivity and/or systemic inflammation, are predictive of attenuated response to ICS therapy. We anticipate this research will extend our understanding of mechanisms relating obesity and asthma while identifying modifiable factors or novel therapeutic strategies to optimize care for this growing proportion of asthma patients. Emerging evidence suggests a relationship between obesity and asthma, although the precise nature of this relationship is not known. We postulate that the systemic inflammatory state associated with obesity may have important biological effects on prognosis and response to therapy in asthma, in part by mediating the development of glucocorticoid insensitivity. We anticipate this research will extend our understanding of mechanisms relating obesity and asthma while identifying modifiable factors or novel therapeutic strategies to optimize care for this growing proportion of asthma patients. (End of Abstract) [unreadable] [unreadable] [unreadable]